Phenylacetonitrile derivatives and hair tonics and external preparations for skin containing the derivatives

ABSTRACT

A hair growth promoting composition comprising, as an effective ingredient, a phenylacetonitrile derivative or a pharmacologically acceptable salt thereof expressed by the following Formula (I):  
                 
 
wherein each of R 1  and R 2  is hydrogen atom, a C 1-10  alkyl group, a C 2-10  alkenyl group or C 2-10  acyl group, or NR 1 R 2  may be a heterocycle having 3-7 members; R 3  is a C 1-5  alkyl group; and each of R 4 , R 5  and R 6  is hydrogen atom or a C 1-4  alkoxy group. The present invention provides a hair growth promoting composition having excellent effects on promoting hair regrowth, preventing or inhibiting hair loss, and the like in human by compounding above-specified phenylacetonitrile derivative as a effective ingredient thereto.

RELATED APPLICATIONS

This application claims the priority of Japanese Patent Application No. 2002-92377 filed on Mar. 28, 2002, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a phenylacetonitrile derivative, and a hair growth promoting composition and external preparation for skin using the same.

BACKGROUND OF THE INVENTION

At the present time, scalp abnormality due to activation of androgen in an organ such as hair root or sebaceous gland, lowering of blood stream toward hair follicle, excess secretion of sebum, formation of peroxide and the like has been considered as a cause of baldness or hair loss. Accordingly, for a long time, a compound or composition that can remove or reduce the above-mentioned problems has been generally included into a hair growth promoting composition (it is also called a hair growth composition, a hair regrowth promoting composition or the like), which purpose is to promote hair growth and regrowth and to prevent hair loss.

At present, compounds or crude drug extracts having various functions have been compounded to the hair growth promoting composition in various combinations. These functions include blood flow promoting action, topical stimulation, hair follicle activating action, antiandrogen action, antiseborrheic action and the like have been known. Examples of drugs having blood flow promoting action include swertia herb extract, vitamin E and its derivative, and benzyl nicotinate. Examples of drugs that promote blood circulation by topical stimulation include capsicum tincture, cantharides tincture, camphor and vanillic acid nonylamide. Examples of drugs having hair follicle activating action include hinokitiol, placental extract, photosensitizing dye, pantothenic acid and derivative thereof. Examples of drugs having antiandrogen action include estradiol and estrone. Examples of drugs having antiseborrheic action include sulfur, thioxolone and vitamin B₆.

In addition, salicylic acid, resorcine and the like that have corneocyte desquamating action and antibacterial action can be compounded to hair growth promoting composition for the purpose of preventing dandruff. Further, glycyrrhizic acid, menthol and the like can be compounded in order to prevent inflammation of scalp. Furthermore, amino acids, vitamins, extracts of crude drugs and the like can be compounded so as to aliment to hair follicle and activate enzyme activity.

Meanwhile, for example, D(L)-pantolactone (Unexamined Japanese Patent Publication No. Hei 8-26942), 2(1H)-pyridone derivative (Unexamined Japanese Patent Publication No. Hei 8-20521), NG-nitro-L-arginine (Unexamined Japanese Patent Publication No. Hei 7-316023), 3-methyleneisoindolin-1-one derivative (Unexamined Japanese Patent Publication No. Hei 7-316022), indole derivative (Unexamined Japanese Patent Publication No. Hei 7-304736) are disclosed in recent patents as drugs having hair regrowth effect, hair growth effect, and hair loss protecting effect.

However, although the drugs described above are compounded to the conventional hair growth promoting compositions, they do not always exhibit sufficient effect.

SUMMARY OF THE INVENTION

The present invention has been performed in view of the foregoing problem in the prior art and its object of the present invention is to provide a compound that is excellent in hair growth promoting effect such as a hair regrowth promoting or hair growing on human hair, and a hair growth promoting composition comprising the same as an active ingredient.

As a result of diligent studies of the inventors for attaining the above-mentioned objects, it has been found that certain phenylacetonitrile derivative has a growth-stimulative effect on hair follicle cell and is useful as a hair growth promoter, thereby accomplishing the present invention.

Namely, a hair growth promoting composition in accordance with the present invention comprises, as an effective ingredient, a phenylacetonitrile derivative or a pharmacologically acceptable salt thereof expressed by the following Formula (I):

wherein

each of R¹ and R² is hydrogen atom, a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group or C₂₋₁₀ acyl group, or NR¹R² may be a heterocycle having 3-7 members;

R³ is a C₁₋₅ alkyl group; and

each of R⁴, R⁵ and R⁶ is hydrogen atom or a C₁₋₄ alkoxy group.

In the hair growth promoting composition of the present invention, it is preferable that said phenylacetonitrile derivative is expressed by the following Formula (I-1):

wherein R¹ and R² are as defined in said Formula (I).

Also, it is preferable that one of R¹ and R² is hydrogen atom or an alkyl group and the other is an alkyl group.

An external preparation for skin in accordance with the present invention comprises a phenylacetonitrile derivative or a pharmacologically acceptable salt thereof expressed by the following Formula (I):

wherein

each of R¹ and R² is hydrogen atom, a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group or C₂₋₁₀ acyl group, or NR¹R² may be a heterocycle having 3-7 members;

R³ is a C₁₋₅ alkyl group; and

each of R⁴, R⁵ and R⁶ is hydrogen atom or a C₁₋₄ alkoxy group.

A phenylacetonitrile derivative in accordance with the present invention is a compound or a pharmacologically acceptable salt thereof expressed by the following Formula (I-2):

wherein each of R⁷ and R⁸ is hydrogen atom, a C₁₋₅ alkyl group or a C₂₋₅ alkenyl group, or NR⁷R⁸ may be a nonaromatic heterocycle having 3-7 members containing one nitrogen atom or an aromatic heterocycle having 5-7 members containing 1-3 nitrogen atoms, and wherein when one of R⁷and R⁸ is hydrogen atom or methyl group, the other is C₂₋₅ alkyl group or C₂₋₅ alkenyl group.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, R¹ and R², which may be identical or different from each other, can be hydrogen atom, a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group or a C₁₋₁₀ acyl group. Also, NR¹R² may be a heterocycle having 3-7 members. Here, in Formula (I) or (I-1), it is preferable that one of R¹ and R² is hydrogen atom or an alkyl group and the other is an alkyl group. More preferably, both of R¹ and R² are alkyl groups.

In R¹ and R², the C₁₋₁₀ alkyl group represents a straight or branched alkyl group having 1-10 carbon atoms, preferably having 1-5 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, tert-butyl, isobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, isopentyl, neopentyl, hexyl, 2-ethylhexyl, heptyl, nonyl and decyl. Also, a part or the whole of the alkyl group may be cyclic. Examples of the cycloalkyl group include cyclopropyl, cyclopentyl and cyclohexyl groups.

In R¹ and R², the C₂₋₁₀ alkenyl group represents a straight or branched unsaturated aliphatic hydrocarbon group having 2-10 carbon atoms containing at least one double bond. Examples thereof include vinyl, allyl, metallyl, 2-pentenyl, 2-butenyl, prenyl, 3-octenyl and 4-decenyl. Also, a part or the whole of the alkenyl group may be cyclic. Examples of the cycloalkenyl group include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl groups.

In the R¹ and R², the acyl group represents a carbonyl group having 1-10 carbon atoms as a total, which has hydrogen atom, an alkyl group, an aryl group or an alkenyl group. Examples thereof include acetyl, propionyl, butyryl, acryloyl, benzoyl, toluoyl and cinnamoyl.

The heterocycle formed by NR¹R² represents a saturated or unsaturated heterocycle having 3-7 members containing the nitrogen atom to which R¹ and R² are bonded. In addition, this heterocycle may contain one or two hetero atoms selected from nitrogen, oxygen and sulfur, respectively. Examples of the heterocycle include aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneimine, homopiperazine, piperazine, morpholine, pyrrole, pyrazole and imidazole rings. Among these heterocycles, pyrrolidine, piperidine, piperazine or morpholine ring is preferable.

In Formula (I), R³ represents a straight or branched alkyl group having 1-5 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, tert-butyl, isobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, isopentyl and neopentyl. Also, a part or the whole thereof may be cyclic. Examples of the cycloalkyl group include cyclopropyl and cyclopentyl groups. R³ is preferably isopropyl group.

In Formula (I), each of R⁴ to R⁶, which may be identical or different from each other, can be hydrogen atom or a C₁₋₄ alkoxy group. The C₁₋₄ alkoxy group represents an oxy group having an alkyl group of 1-4 carbon atoms, which may be straight, branched or cyclic. Examples thereof include methoxy, ethoxy, propyloxy, n-butoxy and tert-butoxy. Preferably, it is methoxy.

In the phenylacetonitrile derivative shown by said Formula (I-2), each of R⁷ and R⁸, which may be identical or different from each other, represents hydrogen atom, a C₁₋₅ alkyl group alkyl group or a C₂₋₅ alkenyl group. Also, NR⁷R⁸ may be a nonaromatic heterocycle having 3-7 members containing one nitrogen atom or a aromatic heterocycle having 5-7 members containing 1-3 nitrogen atoms. However, when one of R⁷ and R⁸ is hydrogen atom or methyl group, the other is C₂₋₅ alkyl group or C₂₋₅ alkenyl group. In Formula (I-2), it is preferably that R⁷ and R⁸ are alkyl groups.

In R⁷ and R⁸, the C₁₋₅ alkyl group represents a straight or branched alkyl group having 1-5 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, tert-butyl, isobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, isopentyl and neopentyl. Also, a part or the whole of the alkyl group may be cyclic. Examples of the cycloalkyl group include cyclopropyl and cyclopentyl groups.

In R⁷ and R⁸, the alkenyl group represents a straight or branched unsaturated aliphatic hydrocarbon group having 2-5 carbon atoms containing at least one double bond. Examples thereof include allyl, metallyl, 2-butenyl and prenyl. Also, a part or the whole of the alkenyl group may be cyclic. Examples of the cycloalkenyl group include cyclopropenyl, cyclobutenyl and cyclopentenyl groups.

The nonaromatic heterocycle formed by NR⁷R⁸ represents a saturated or unsaturated nonaromatic heterocycle having 3-7 members containing the nitrogen atom to which R⁷ and R⁸ are bonded. In addition, this nonaromatic heterocycle may contain one or two hetero atoms selected from oxygen and sulfur, respectively. Examples of the nonaromatic heterocycle include aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneimine and morpholine rings. Among them, pyrrolidine, piperidine, piperazine or morpholine ring is preferable.

The aromatic heterocycle formed by NR⁷R⁸ represents an aromatic heterocycle having 5-7 members containing the nitrogen atom to which R⁷ and R⁸ are bonded. In addition, this aromatic heterocycle may contain one or two nitrogen atoms. Examples of the aromatic heterocycle include pyrrole, imidazole, pyrazole and triazole rings. Among them, pyrrole, imidazole or pyrazole ring is preferable.

The hair growth promoting composition or the external preparation for skin is characterized by comprising a phenylacetonitrile derivative of said Formula (I).

Japanese Patent No. 2569088, Unexamined Japanese Patent Publication No. Sho 62-167752, Examined Japanese Patent Publication No. Hei 4-49538 and Unexamined Japanese Patent Publication No. Hei 3-291261 disclose phenylacetonitrile derivatives which have a calcium antagonism action or serotonin-bonding action and is useful as a drug for treating coronary artery disease or hypertension. Also, Unexamined Japanese Patent Publication No. 4-500067 discloses phenylacetonitrile derivatives effective for destructing anticancer drug resistance.

However, it is not disclosed in any publications mentioned above that the phenylacetonitrile derivative expressed by said Formula (I) of the present invention has a hair growth promoting effect and is applied to an external preparation for skin.

A preferable example of the phenylacetonitrile derivative (I), which is compounded in the hair growth promoting composition or the external preparation for skin of the present invention, is a compound expressed by said Formula (I-1).

Also, among phenylacetonitrile derivative (I), the compound of said Formula (I-2) has not been reported until now. Therefore, it is a novel.

The phenylacetonitrile derivative expressed by Formula (I) of the present invention may have one or more asymmetric centers. The present invention can include enantiomer, diastereomer and a mixture thereof based on the asymmetric carbon. Also, when there are the other isomers such as conformational isomers and geometrical isomers, the present invention can include them.

As long as effects of the present invention can be exhibited, the alkyl group, alkenyl group and heterocycle having 3-7 carbon atoms in said R¹ and R² can have at least one substituent (e.g. 1-5 substituents) at a feasible position. Examples of the substituent include a C₃-8 cycloalkyl, hydroxy, mercapto, cyano, carbamoyl, carboxyl, a C₁₋₄ alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl and the like), halogen (fluorine, chlorine, bromine, iodine), a group expressed by —(OA¹)n—OA², wherein A¹ is a C₁₋₄ alkylene, A² is a C₁₋₄ alkyl, and n is an integer of 0-3 (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, ethoxyethoxy, methoxyethoxyethoxy and the like), phenoxy, halogenophenoxy (e.g., o-, m- or p-chlorophenoxy, o-, m- or p-bromophenoxy and the like), a C₁₋₄ alkylhthio (e.g., methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, and the like), phenylthio, a C₁₋₄ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and the like), a C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like), a C₁₋₁₀ haloalkyl (e.g., difluoromethyl, trifluoromethyl, trifluoroethyl, trichloroethyl and the like), formyl, a C₁₋₅ alkanoyl (e.g., acetyl and the like) and benzoyl.

In addition, examples of the substituent can include an unsubstituted or substituted amino, i.e., a C₁₋₄ alkanoylamino (e.g., acetylamino, propionylamino and the like), a C₁₋₃₀ alkylamino (e.g., methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino, undecylamino, dodecylamino, tridecylamino, tetradecylamino, pentadecylamino, hexadecylamino, heptadecylamino, octadecylamino, nonadecylamino, icosylamino, henicosylamino, docosylamino, tricosylamino, tetracosylamino, pentacosylamino, hexacosylamino, heptacosylamino, octacosylamino, nonacosylamino, triacontylamino and the like, in which the alkyl group may be substituted with hydroxy group), a di-C₁₋₄ alkylamino (e.g., dimethylamino, diethylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino and the like).

Further, examples of the substituent can include a heterocycle group having 5 or 6 members, e.g., an unsubstituted or substituted heterocycle group containing 1-4 hetero atoms selected from oxygen, sulphur and nitrogen atoms. Examples of the heterocycle include pyrrolidyl, piperidyl, morpholino, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, imidaquinolyl and indolyl. These heterocycle group having 5 or 6 members is generally substituted with a C₁₋₂ hydrocarbon. Also, examples of the heterocycle can include a heterocycle group substituted with 1-4 substituents such as halogen (fluorine, chlorine, bromine, iodine and the like), a C₁₋₄ alkyl (methyl, ethyl, propyl, isopropyl, and the like) and halogenophenoxy (o-, m-, or p-chlorophenoxy, o-, m-, or p-bromophenoxy and the like).

The alkyl group, alkenyl group, nonaromatic heterocycle and aromatic heterocycle in said R⁷ and R⁸ can have at least one substituent, e.g., 1-5 substituents, at a feasible position. Examples of the substituent include hydroxy, mercapto, cyano, halogen (fluorine, chlorine, bromine, iodine), a C₁₋₄ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-methoxyethoxy and the like), a C₁₋₄ alkylthio (e.g., methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio and the like), a C₁₋₄ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl and the like), a C₁₋₄ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like) and a C₁₋₁₀ haloalkyl (e.g., difluoromethyl, trifluoromethyl, trifluoroethyl, trichloroethyl and the like).

In addition, examples of the substituent can include an unsubstituted or substituted amino, i.e., a C₁₋₆ alkanoylamino (e.g., acetylamino, propionylamino and the like), a C₁₋₁₀ alkylamino (e.g., methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino and the like, in which the alkyl group may be substituted with hydroxy group), a di-C₁₋₄ alkylamino (e.g., dimethylamino, diethylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino and the like).

Compound (I) can be manufactured by using known reactions. Although the representative synthetic examples will be shown in below, the present invention is not restricted thereto. In the following manufacturing methods, R¹ and R² can be replaced with R⁷ and R⁸ to be read. Also, R¹, R², R⁷ and R⁸ are as shown in definitions mentioned above, unless otherwise indicated. In order to obtain the compound as an optically active substance, an optically active material, reagent, catalyst or the like may be used. Also, at a suitable step, a separating operation such as chromatography or fractional crystallization may be performed. Further, when there are a conformational isomer and a geometrical isomer, a starting material and a reaction condition can be selected suitably and then separating operation can be performed to obtain a pure conformational isomer or a geometrical isomer. Furthermore, when there is a functional group in the molecule and said functional group becomes or in danger of a disturbance of reaction, it is preferable that a suitable protecting group is used to put the reaction forward effectively. Use of protecting group can be performed, for example, according to Protective Groups in Organic Synthesis by Theodora W. Greene, Peter G. M. Wuts et al. Also, unless there is any problem, a reaction condition and order of process can be changed, thereby selecting more suitable method.

Compound (I-1) can be synthesized, for example, as shown in Scheme 1, wherein dimethoxyphenylacetonitrile (III) is reacted with 2-substituted propane to give Compound (IV), this Compound (IV) is reacted with 1,3-disubstituted propane to give Compound (V), and then Compound (V) is reacted with an amine to give Compound (I-1). Each of X and X′ represents a leaving group, which may be identical or different from each other. Examples of the leaving group include a halogen atom such as fluorine, chlorine, bromine, iodine or the like, mesyl group and tosyl group. In the following, the definitions of X and X′ is the same unless otherwise specified.

As a 2-substituted propane used in the reaction with dimethoxyphenylacetonitrile (III), for example, 2-chloropropane, 2-bromopropane or 2-iodopropane can be used. The reaction can be usually performed in the presence of a base such as metallic sodium, sodium hydride or sodium amide with or without a solvent. As a solvent, an aromatic carbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoramide; acetonitrile, dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of −15° C. to the reflux temperature of the solvent. Specifically, for example, Compound (III) and isopropyl bromide are reacted in tetrahydrofuran in the presence of sodium amide at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

As a 1,3-disubstituted propane used in the reaction with Compound (IV), for example, 1-chloro-3-iodopropane, 1-bromo-3-iodopropane, 1-bromo-3-chloropropane, 1,3-dichloropropane, 1,3-dibromopropane or 1,3-diiodopropane can be used. The reaction can be usually effected in the presence of a base such as metallic sodium, sodium hydride or sodium amide with or without a solvent. As a solvent, an aromatic carbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of −15° C. to the reflux temperature of the solvent. Specifically, for example, Compound (IV) and 1-chloro-3-iodopropane are reacted in toluene in the presence of sodium amide at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

The reaction of Compound (V) with the amine NR¹R² can be usually effected in the presence of a base. As a base, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, or an organic base such as butyl lithium can be used. As a solvent, an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an alcohol such as methanol or ethanol; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of 0° C. to the reflux temperature of the solvent. Specifically, for example, Compound (V) and the amine are reacted in N,N-dimethylacetamide in the presence of potassium carbonate at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

Also, Compound (I-1) can be synthesized, as shown in Scheme 2, by a reaction of Compound (VI) obtained from amine NR¹R² and 1,3-disubstituted propane with Compound (IV).

The reaction of the amine NR¹R² with 1,3-disubstituted propane can be usually effected in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, or an organic base such as butyl lithium with or without a solvent. As a solvent, an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an alcohol such as methanol or ethanol; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of 0° C. to the reflux temperature of the solvent. Specifically, for example, the amine and 1-chloro-3-iodopropane are reacted in N,N-dimethylacetamide in the presence of potassium carbonate at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

The reaction of Compound (VI) with Compound (IV) may be effected according to said reaction of Compound (IV) with a 1,3-disubstituted propane. Namely, it can be effected in the presence of a base such as metallic sodium, sodium hydride or sodium amide with or without a solvent. As a solvent, an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of −15° C. to the reflux temperature of the solvent. Specifically, for example, Compound (IV) and Compound (VI) are reacted in toluene in the presence of sodium amide at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

The synthesis of Compound (I-1) from Compound (V) can be effected by a method shown in Scheme 3.

The reaction of Compound (V) with monoalkylamine can be effected according to the said reaction of Compound (V) with the amine. Namely, it can be effected in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, or an organic base such as butyl lithium in a solvent. As a solvent, an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an alcohol such as methanol or ethanol; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of 0° C. to the reflux temperature of the solvent. Specifically, for example, Compound (V) and monoalkylamine are reacted in N,N-dimethyl acetamide in the presence of potassium carbonate at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

The reaction of Compound (VII) with the substituted alkyl is usually effected in the presence of a base with or without a solvent. The base used in this reaction can be an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, or an organic base such as butyl lithium. As a solvent, an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an alcohol such as methanol or ethanol; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of 0° C. to the reflux temperature of the solvent. Specifically, for example, Compound (VII) and the alkyl bromide are reacted in N,N-dimethylacetamide in the presence of potassium carbonate at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

Also, the synthesis of Compound (I-1) from Compound (IV) can be effected by a method shown in Scheme 4.

The reaction of Compound (IV) with Compound (VIII) is usually effected in the presence of a base. Each of P¹ and P² represents a carbonyl-protecting group, which may be identical or different from each other. Examples of the protecting group include a lower alkyl group. Also, P¹ and P² may together form a C₂₋₆ alkylene group. As a base, metallic sodium, sodium hydride, sodium amide or the like can be used. The reaction is effected with or without a solvent, which can be an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide or the like. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of −15° C. to the reflux temperature of the solvent. Specifically, for example, Compound (IV) and Compound (VIII) are reacted in toluene in the presence of sodium amide at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

The synthesis of Compound (X) by deprotecting Compound (IX) is usually effected in the presence of acid catalyst. As an acid catalyst, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, aluminum chloride, titanium tetrachloride, iron chloride or trifluoroborane, or an organic acid such as oxalic acid or titanium tetraisopropoxide can be used. The reaction is usually effected with or without a solvent. As a solvent, an aromatic hydrocarbon such as benzene, toluene or xylene; an ether such as tetrahydrofuran or 1,4-dioxane; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetone; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of 0° C. to the reflux temperature of the solvent. Specifically, for example, Compound (IX) and oxalic acid are mixed in acetone and reacted at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

The synthesis of Compound (I-1) by reductive amination of Compound (X) with the amine is usually effected in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium trimethoxyborohydride with a solvent. As a solvent, an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or 1,4-dioxane; and amide such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; acetonitrile; dimethyl sulfoxide and the like can be used. While the reaction temperature and reaction time may be changed according to the starting materials and the reagents used, the reaction is usually effected at a temperature within the range of 0° C. to the reflux temperature of the solvent. Specifically, for example, Compound (X) and the amine are mixed in methanol and reacted, with sodium cyanoborohydride added thereto little by little, at a temperature within the range of room temperature to the reflux temperature, thereby attaining the aimed object.

In any reaction mentioned above, a catalyst, a halogen-exchanging agent, a pH adjusting agent, a cosolvent or the like can be added, if necessary. The starting materials used in the foregoing Reaction Formulae are commercially available or can be synthesized from a suitable starting material by using known methods.

In the present invention, Compound (I) can be changed to an acid-added salt if necessary. Examples of the acid-added salt include salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid and salts with an organic acid such as acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid or methanesulfonic acid. These salts can be easily manufactured by common methods.

Compound (I), which mechanism of action has not been made clear, have an excellent hair follicle cell growth-simulative effect. Therefore, it is useful for a hair growth promoting composition (which is a general idea including hair growth composition, hair regrowth promoting composition and the like), which purpose is to promote hair growth and regrowth and to prevent hair loss in human. By applying it on scalp, care, improvement or prevention of hair loss can be expected.

The hair growth promoting composition comprising Compound (I) of the present invention can apply to pathological alopecia such as alopecia areata, alopecia pityrodes or alopecia seborrheica in addition to thin hair or hair loss what is called male pattern baldness or androgenic alopecia. The dosage of the compound (I) must be determined suitably according to sex, age and degree of symptom in hair loss or thin hair. Usually 0.01-20 mg/cm² is applied on scalp per day for an adult in a single dose or several doses.

The hair promoting composition of the present invention can be used as a drug, quasi-drug or cosmetic external preparation, which purpose is to promote hair growth and regrowth and to prevent hair loss. The pharmaceutical form can be selected voluntarily as long as the effects of the present invention can be exhibited. Examples of the pharmaceutical form include a tonic, a lotion, a milky lotion, a cream, an ointment, a gel, an aerosol, a spray and a mousse. The product form can be also selected freely. For example, it may be a hair regrowth promoting composition, a hair growth composition, a scalp treatment, a hair tonic, a shampoo, a rinse, a hair pack, a hair lotion, a conditioner, and a scalp treatment.

Compound (I), which is not restricted as long as the present effect is spoiled, is usually 0.001-20% by weight, preferably 0.01-5% by weight in the hair growth promoting composition or external preparation for skin of the present invention. When the compounding amount is too less, it may be lead to an insufficient effect of the present invention. On the other hand, when the compounding amount is too much, it may be lead to a pharmaceutically unfavorable composition. In the present invention, two or more of Compound (I) may be compounded in combination.

In addition to Compound (I), if necessary, ingredients normally used in the field of drug, quasi-drug and cosmetic can be compounded to the hair growth promoting composition and external preparation for skin of the present invention as long as the present effect is not spoiled. Examples of drugs having a blood flow promoting action include swertia herb extract, vitamin E and derivatives thereof, nicotinates such as benzyl nicotinate. Examples of drugs that promote blood circulation by topical stimulation include capsicum tincture, cantharides tincture, camphor and vanillic acid nonylamide. Examples of drugs having hair follicle activating action include hinokitiol, placental extract, photosensitizing dye, pantothenic acid and derivatives thereof. Examples of drugs having antiandrogen action include a hormone such as estradiol or estrone. Examples of drugs having antiseborrheic action include sulfur, thioxolone and vitamin B₅.

In addition, salicylic acid, resorcine and the like which has corneocycle desquamating and antibacterial action can be compounded therein so as to prevent the generation of dandruff. Also, glycyrrhizic acid and derivatives thereof, menthol, and the like can be compounded therein so as to prevent inflammation of scalp. Further, an amino acid such as serine, methionine or arginine, a vitamin such as biotin, extracts of crude drugs and the like can be compounded therein in order to supplement nutrition for hair follicle and activate enzyme activity.

Also, extracts from plants such as althea, coix, peppermint, leaf base, capsicum, aloe, lycium, mugwort, oryza, seashore vitex, rosmarinus officinalis, drynaria, cytisus scoparius, gentiana, salviae miltiorrhizeae radix, sponge gourd, platycodon, pinus, sophora root, Japanese angelica root, safflower, Japanese barberry, areca, eucalyptus, prunella spike, akebia stem, achyranthes root, bupleurum root, tea, licorice, hop, Chrysanthemum, senega, sesame, cnidium rhizome, cashew, pueraria root, rosae rugosae flos, saffron, rosemary, rehmannia root, or mallow can be compounded.

Also, a vasodilator such as alkoxycarbonylpyridine N-oxide, carpronium chloride or acetylcholine derivative; a cutaneous hyperfunctioning agent such as cephalanthin; an antibacterial agent such as hexachlorophene, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide or bithionol; zinc and its derivatives; lactic acid and its alkyl ester; an organic acid such as citric acid; a protease inhibitor such as tranexamic acid; and the like can be compounded. Other drugs may be compounded thereto.

Further, an alcohol such as ethanol or isopropanol; a polyvalent alcohol such as glycerin, propylene glycol or polyethylene glycol; an oily ingredient such as higher fatty acids, higher alcohols, hydrocarbons, natural oils and fats, ester oils or silicone oils; surfactants; perfumes; chelating agents; humectants such as 1,3-butyleneglycol, hyaluronic acid and its derivatives, maltitol, soluble collagen or sodium lactate; thickening agents such as quince mucilage, carboxyvinyl polymer or xanthan gum; antioxidants; ultraviolet absorbers: coloring agents; water; stabilizers; powders; water-soluble macromolecular compounds; coating materials; and the like can be compounded.

EXAMPLES

In the following, the present invention will be further explained by specific examples. However, the present invention should not be restricted thereto. The compounding amount and concentration were shown by weight % unless otherwise specified.

Experiment 1

Growth-Stimulative Activity Test on Immortalized Human Outer Root Sheath Cell

(I) Immortalized Human Outer Root Sheath Cell

Keratinocyte-SFM medium (Gibco BRL), to which a supplement attached with the medium was added, was used for culture on a dish which surface was coated with collagen. The cell was cultured until it became semiconfluent and then peeled off with 0.05% trypsin/PBS(−) and subcultured. 30-40^(th) stage culture cells were used for study on growth.

(2) Sample Preparation

Each tested compound described below is dissolved with distilled water at the concentration of 10 mM and sterilized through Millipore filter. This aqueous solution was diluted with KBM at a predetermined concentration and added to the cell as a sample.

Tested Compound

Example 21

-   2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[methyl(3-methylbutyl)amino]-pentanenitrile     hydrochloride

Example 22

-   (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-(methylamino)pentanenitrile     hydrochloride

Example 23

-   (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[methyl(3-methylbutyl)amino]-pentanenitrile     hydrochloride     (3) Evaluation of Growth-Stimulative Activity on Immortalized Human     Outer Root Sheath Cell

The immortalized human outer root sheath cell was inoculated into a microplate (Iwaki, 24 wells) (20000 cells/well) with a growth medium KGM (Sanko Junyaku Co., Ltd., CC-3111) and incubated at 37° C. for 1 day. After each well was washed once with basal medium KBM (Sanko Junyaku Co., Ltd., CC-3101), the medium was exchanged with KBM containing each sample, and then incubated further for 2 days. [³H]-Thymidine (Amersham Pharmacia Biotech K.K., TRK758, the final concentration: 20 μCi/ml) was added thereto and incubated at 37° C. for 3 hours. The cell was peeled off with 0.25% trypsin/PBS(−) and collected on a glass filter (Watmann, GLC). After [³H]-thymidine that is not taken into the cell was removed by washing with distilled water, the filter was air-dried and then the radioactivity was measured by a liquid scintillation counter.

(4) Result

In a experiment adding each sample at a concentration within a range of 10⁻⁹-10⁻¹³M, using the uptake quantity of radioactivity in the sample-added group when that in the negative control medium (KBM+dH₂O) was regarded as 100%, the immortalized human outer root sheath cell growth activity was evaluated. The results were shown in Table 1. TABLE 1 [³H]-thymidine Tested compound Concentration uptake quantity Negative control — 100% Example 21 10⁻⁹ M 151% ″ 10⁻¹⁰ M 143% ″ 10⁻¹¹ M 160% ″ 10⁻¹² M 114% ″ 10⁻¹³ M 118% Example 22 10⁻⁹ M 105% ″ 10⁻¹⁰ M  98% ″ 10⁻¹¹ M 111% ″ 10⁻¹² M 135% ″ 10⁻¹³ M 153% ″ 10⁻¹⁴ M 160% Example 23 10⁻⁹ M 115% ″ 10⁻¹⁰ M 106% ″ 10⁻¹¹ M 107% ″ 10⁻¹² M 117% ″ 10⁻¹³ M 114% ″ 10⁻¹⁴ M 125%

As evident from Table 1 above, it can be understood that a phenylacetonitrile derivative in accordance with the present invention shows a growth-stimulative activity on immortalized human outer root sheath cell and is useful as a hair growth promoter.

Experiment 2

Growth-Stimulative Activity Test on Artificial Human Bulbus Pili Cell

(1) Preparation of First Stage Incubated Outer Root Sheath Cell

A bulbus pili site of a hair follicle isolated from a human scalp obtained by a plastic surgery was excised and then enzymatically treated in Keratinocyte-SFM medium (GibcoBRL:11965-011) supplemented with 1000 unit/ml dispase+0.2% collagenase at 37° C. for 30 minutes. After unnecessary hair follicle mesenchymal tissue such as connective tissue root sheath was removed therefrom using the tip of a syringe needle (27G), the residue was placed in the incubating space of an incubator coated with collagen and explant culture was performed in Keratinocyte-SFM medium supplemented with an antibacterial agent. After incubation for about 1 week, the medium was exchanged upon ensuring the growth of the cells. Cells grown to be subconfluent were treated with PBS(−)+0.05% trypsin at 37° C. for 3 minutes and the reaction was stopped with an equivalent amount or more of PBS(−)+0.1% trypsin inhibitor (Sigma). The cells were collected by centrifugal separation (1200 rpm×5 min) and suspended again in PBS(−). The cells were collected by centrifugal separation (1200 rpm×5 min), thereby washing the cells. Washed cells were stored while being frozen in a liquid nitrogen using Cellbanker II (DIA-IATRON: ZCB-201(100)), thereby obtaining the first stage incubated outer root sheath cells.

(2) Preparation of First Stage Incubated Dermal Papilla Cell

From a bulbus pili site obtained by excising a hair follicle isolated from a human scalp obtained by a plastic surgery, using the tip of a syringe needle (27G), a dermal papilla site was isolated under a stereoscopic microscope and placed in the incubating space of an incubator coated with collagen. Then, explant culture was performed in 10% FBS-added DMEM medium (GibcoBRL: 11965-092) supplemented with an antibacterial agent. After incubation for about 2 week, the medium was exchanged upon ensuring the growth of the cells. Cells grown to be subconfluent were treated with PBS(−)+0.05% trypsin at 37° C. for 3 minutes and the reaction was stopped with an equivalent amount or more of PBS(−)+0.1% trypsin inhibitor (Sigma). The cells were collected by centrifugal separation (1200 rpm×5 min) and suspended again in PBS(−). The cells were collected by centrifugal separation (1200 rpm×5 min), thereby washing the cells. Washed cells were stored while being frozen in a liquid nitrogen using Cellbanker II (DIA-IATRON: ZCB-201(100)), thereby obtaining the first stage incubated dermal papilla cells.

(3) Manufacture of the Artificial Bulbus Pili Site

The first stage incubated dermal papilla cell obtained above was subcultured three times (37° C., 5% CO₂) in a 10% FBS-supplemented DMEM medium (GibcoBRL: 11965-092) in a 75 cm² incubation flask coated with Type I collagen, and then stored while being frozen in a liquid nitrogen using Cellbanker II (DIA-IATRON: ZCB-201(100)) (DPc).

Also, the first stage incubated outer root sheath cell obtained above was subcultured three times (37° C., 5% CO₂) in a Keratinocyte-SFM medium (GibcoBRL: 11965-011) in a 75 cm² incubation flask coated with Type I collagen, and then stored while being frozen in a liquid nitrogen using Cellbanker II (DIA-IATRON: ZCB-201(100)) (ORSc).

The DPc and ORSc stored as frozen were thawed, washed with an ice-cooled Keratinocyte-SFM medium, dispersed in Keratinocyte-SFM(+) medium (which is Keratinocyte-SFM medium supplemented with 5 ng/mL epidermal growth factor and 5 μl/mL bovine pituitary glanusi extract), and subjected to an accurate cell density measurement using a hemocytometer. Then, each cell density was adjusted at 5×10⁴ cells/ml, and the cell dispersions in equal volumes were combined under cooling with ice. 80 μl aliquots of the combined cell suspending Keratinocyte-SFM(+) medium were inoculated into individual wells of Sumilon celltight spheroid 96U plate (Sumitomo Bakelit co.,), and incubated for 2 days (37° C., 5% CO₂). A cell in a condition that an ORSc was attached around a cell cluster of DPc was sorted out, to manufacture the artificial bulbus pili site by one-step process.

(4) Addition of Test Material and Measurement of Activity

Each 80 μl of a test material-supplemented William's E(+) medium (which is William's E medium supplemented with 10 μg/ml transferrin, 10 ng/ml hydrocortisone, 10 μg/ml insulin and 10 ng/ml sodium selenite) was added to each well and incubated at 37° C. under 5% CO₂ further for 2 days.

The test material-supplemented William's E(+) medium was prepared by dissolving the test material in ethanol at a concentration of 10⁻⁹ M or 10⁻¹¹ M and adding to William's E(+) medium at 0.2% each. Accordingly, the final concentration of the test material in each well was 10⁻¹² M or 10−¹⁴ M, and each final concentration of ethanol was 0.1%.

As a negative control, 80 μl of William's E(+) medium containing 0.2% ethanol was added (the final concentration of ethanol was 0.1%).

After incubation, Alamer Blue (Biosource: DAL1100), Keratinocyte-SFM medium and William's E(+) medium were mixed in 2:1:1 ratio (volume ratio), warmed at 37° C. and then 40 μl aliquots were added to individual wells and allowed to react at 37° C. for 6 hours. After completion of the reaction, 100 μl aliquots were taken from individual wells, and transferred to each well of a white 96-well plate for fluorescence measurement (Opaque Plate) (Coster:3912).

A fluorometer (Labsystems Fluoroskan II) was used at the excitation wavelength of 544 nm and the fluorescent wavelength of 590 nm to measure the fluorescence intensity of each well, from which the fluorescent intensity of a cell-free reaction mixture (i.e., the mixture itself) was subtracted to obtain a respiration level under each condition. A relative respiration level (%) was calculated according to the following equation. Relative respiration level (%)={Respiration level (test material)}/{Respiration level (negative control)}×100

Using the relative respiration level as an index, the cell growth-stimulative effect on an artificial bulbus pili site was judged. Judgment standard is as follows: TABLE 2 Example No. Judgment 4 +++ 5 + 6 + 7 + 8 ++ 9 + 12 + 15 + 16 + 17 ++ 18 +++ 24 ± 25 ++ 26 + 27 + 28 ++ −: No effect (the relative respiration level is less than 102%). ±: Weak effect is recognized (102% or more, and less then 105%). +: Effect is recognized (105% or more, and less then 110%). ++: Strong effect is recognized (110% or more, and less than 115%). +++: Very strong effect is recognized (115% or more). (5) Result

As evident from Table 2 above, it was suggested that a phenylacetonitrile derivative of the present invention showed a cell growth-stimulative activity in the test using an artificial bulbus pili site and was useful as an hair growth promoter. Especially, Examples 8, 17, 25 and 28 showed strong effects, and Examples 4 and 18 showed very strong effects.

Example 1 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile

(1) Synthesis of 2-(3′,4′-dimethoxyphenyl)-3-methylbutyronitrile

17.70 g (100 mmol) of 3,4-dimethoxyacetonitrile was dissolved in 100 ml of anhydrous tetrahydrofuran, and 4.68 g (120 mmol) of sodium amide was added thereto in fractional amounts while being stirred and cooled with ice. After being stirred for 30 minutes, 14.76 g (120 mmol) of 2-bromopropane was dropwise added to the mixture and then stirred with heating at 60° C. for 1 hour. After disappearance of the starting material was checked, a small amount of methanol was added to the mixture to decompose excess sodium amide, and the solvent was evaporated out under a vacuum. The residue was extracted with ethyl acetate and then washed with water until it became neutral. The organic layer was filtrated through 1PS filter paper, and then the solvent was evaporated out. The residue was purified by silica gel column chromatography, to give 17.8 g (81 mmol, 81%) of 2-(3′,4′- dimethoxyphenyl)-3-methylbtyronitrile.

¹H-NMR (δ, CDCl₃):1.05 (6H, d, J=6.6Hz), 2.00-2.15 (1H, m), 3.59 (1H, d, J=6.6Hz), 3.89 (3H, s), 3.90 (3H, s), 6.76-6.86 (3H, m).

(2) Synthesis of 5-chloro-2-(3′,4′-dimethoxyphenyl)-2-isopropylpentanenitrile

10.16 g (50 mmol) of 2-(3′,4′-dimethoxyphenyl)-3-methylbutyronitrile was dissolved in 80 ml of anhydrous toluene, and 3.90 g (100 mmol) of sodium amide was added in fractional amounts while being stirred. After being heated and refluxed at 120° C. for 2 hours, the mixture was cooled down to 80° C. and, with 15.33 g (75 mmol) of 1-chloro-3-iodopropane added thereto, further stirred at 80° C. for 1 hour. After disappearance of the starting material was checked, a small amount of methanol was added to the mixture to decompose excess sodium amide, and the solvent was evaporated out under a vacuum. The residue was extracted with ethyl acetate and then washed with water until it became neutral. The organic layer was filtrated through 1PS filter paper, and then the solvent was evaporated out. The residue was purified by silica gel column chromatography, to give 12.03 g (41 mmol, 81%) of 5-chloro-2- (3′,4′-dimethoxyphenyl)-2-isopropylpentanenitrile.

¹H-NMR (δ, CDCl₃):0.82 (3H, d, J=6.7Hz), 1.21 (3H, d, J=6.7Hz), 1.38-1.54 (1H, m), 1.80-1.98 (1H, m), 2.00-2.30 (3H, m), 3.45-3.54 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 6.82-6.96 (3H, m).

(3) Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile

10.40 g (35 mmol) of 5-chloro-2-(3′,4′-dimethoxyphenyl)-2-isopropylpentanenitrile was dissolved in 50 ml of anhydrous ethanol, and 14.50 g (105 mmol) of potassium carbonate, 18.00 g (175 mmol) of 30% methylamine methanol solution and 0.50 g of sodium iodide were added thereto. Then, the mixture was sealed in a tube and stirred at 100° C. for 72 hours. After the solvent was evaporated out under a vacuum, the residue was extracted with ethyl acetate and washed with water three times until it became neutral. The organic layer was acidified with 50 ml of 2N hydrochloric acid, and the water layer was collected. After further three times extraction with 2N hydrochloric acid, the water layers were combined and basified with 48% sodium hydroxide aqueous solution while being cooled with ice, and then extracted three times with 50 of ethyl acetate. The organic layer was filtrated through 1PS filter paper, and the solvent was evaporated out, to give 7.36 g (25 mmol, 72%) of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile.

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.5Hz), 1.20 (3H, d, J=6.5Hz), 1.14-1.23 (1H, m), 1.54-1.61 (1H, m), 1.86-1.95 (1H, m), 2.08 (1H, sept, J=6.5Hz), 2.14-2.22 (1H, m), 2.27 (1H, br-s), 2.37 (3H, s), 2.51-2.61 (2H, m), 3.88 (3H, s), 3.90 (3H, s), 6.83-6.6.87 (2H, m), 6.91-6.95 (1H, m).

Example 2 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methylbutyl)amino]-pentanenitrile

2.03 g (7.0 mmol) of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile was dissolved in 7 ml of dimethylformamide, and 1.45 g (10.5 mmol) of potassium carbonate was added thereto. After being stirred at room temperature for 10 minutes, the mixture, with 1.59 g (10.5 mmol) of isopentyl bromide added thereto, was stirred at room temperature for 16 hours. The solvent was evaporated out under a vacuum, and the residue was extracted with dichloromethane and washed with water until it became neutral. The organic layer was filtrated through 1PS filter paper, and the solvent was evaporated out. The residue was purified by silica gel column chromatography, to give 1.84 g (5.1 mmol, 73%) of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methylbutyl)amino]-pentanenitrile.

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.86 (3H, d, J=6.8Hz), 0.87 (3H, d, J=6.8Hz), 1.10-1.19 (1H, m), 1.19 (3H, d, J=6.8Hz), 1.25-1.32 (2H, m), 1.46-1.57 (2H, m), 1.84 (1H, dt, J=4.4, 12.2Hz), 2.08 (3H, s), 2.03-2.34 (6H, m), 3.88 (3H, s), 3.89 (3H, s), 6.83-6.87 (2H, m), 6.91-6.95 (1H, m).

Examples 3-10

In Example 2, in the place of isopentyl bromide, an alkyl halide shown in Table 2 below can be used to synthesize each compound of Examples 3-10. In the Table, Ms represents mesyl group. TABLE 2

Example R²⁻¹ Alkyl halide 3 -Me MeI 4 -Et EtBr 5 -n-Pr n-PrBr 6 -i-Pr i-PrBr 7 -n-Bu n-BuBr 8 -i-Bu i-BuBr 9 -EtOEt EtOEtCl 10 -EtOEtOMe MeOEtOEtOMs

The ¹H-NMR chemical shifts of Examples 3-10 are shown below.

Example 3

¹H-NMR (δ, CDCl₃):0.79 (3H, d, J=6.8Hz), 1.09-1.18 (1H, m), 1.20 (3H, d, J=6.8Hz), 1.49-1.57 (1H, m) 1.89 (1H, dt, J=4.4, 12.8Hz), 2.09 (1H, sept, J=6.8Hz), 2.12 (6H, s), 2.08-2.21 (2H, m), 2.28 (1H, dt, J=12.2, 7.3Hz), 3.89 (3H, s), 3.89 (3H, s), 6.83-6.86 (2H, m), 6.92-6.96 (1H, m).

Example 4

¹H-NMR (δ, CDCl₃): 0.79 (3H, d, J=6.8Hz), 1.00 (3H, t, J=6.8Hz), 1.11-1.20 (1H, m) 1.19 (3H, d, J=6.8Hz), 1.50-1.58 (1H, m), 1.86 (1H, dt, J=4.4, 12.2Hz), 2.09 (3H, s), 2.03-2.16 (2H, m), 2.21-2.37) (4H, m), 3.89 (3H, s), 3.89 (3H, s), 6.84-6.86 (2H, m), 6.91-6.95 (1H, m).

Example 5

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.85 (3H, t, J=7.3Hz), 1.07-1.21 (1H, m) 1.19 (3H, d, J=6.8Hz), 1.36-1.57 (3H, m), 1.85 (1H, dt, J=4.4, 12.7Hz), 2.09 (3H, s), 2.03-2.34 (6H, m), 3.89 (3H, s), 3.89 (3H, s), 6.83-6.86 (2H, m), 6.91-6.96 (1H, m).

Example 6

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.93 (3H, d, J=6.3Hz), 0.94 (3H, d, J=6.3Hz), 1.06-1.18 (1H, m) 1.19 (3H, d, J=6.8Hz), 1.45-1.56 (1H, m), 1.86 (1H, dt, J=4.4, 12.7Hz), 2.03-2.15 (2H, m), 2.06 (3H, s), 2.31 (3H, t, J=7.0Hz), 2.72 (1H, sept, J=6.3Hz), 3.88 (3H, s), 3.89 (3H, s), 6.82-6.86 (2H, m), 6.92-6.94 (1H, m).

Example 7

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.89 (3H, t, J=7.3Hz), 1.08-1.22 (1H, m) 1.19 (3H, d, J=6.8Hz), 1.23-1.30 (2H, m), 1.33-1.43 (2H, m), 1.45-1.57 (1H, m), 1.85 (1H, dt, J=4.4, 12.7Hz), 2.03-2.34 (6H, m), 2.09 (3H, s), 3.88 (3H, s), 3.89(3H, s), 6.83-6.86 (2H, m), 6.91-6.94 (1H, m).

Example 8

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.85 (6H, t, J=6.3Hz), 1.06-1.17 (1H, m) 1.19 (3H, d, J=6.8Hz), 1.43-1.61 (1H, m), 1.68 (1H, sept, J=6.8Hz), 1.86 (1H, dt, J=4.4, 12.2Hz), 1.95 (2H, d, J=7.3Hz), 2.05 (3H, s), 2.05-2.28 (4H, m), 3.89 (3H, s), 3.90 (3H, s), 6.83-6.87 (2H, m), 6.91-6.95 (1H, m).

Example 9

¹H-NMR (δ, CDCl₃):0.79 (3H, d, J=6.8Hz), 1.08-1.19 (1H, m), 1.19 (3H, t, J=7.0Hz), 1.19 (3H, d, J=6.8Hz), 1.47-1.57 (1H, m), 1.87 (1H, dt, J=4.4, 12.2Hz), 2.03-2.15 (2H, m), 2.16 (3H, s), 2.27-2.53 (4H, m), 3.44-3.50 (4H, m), 3.89 (3H, s), 3.89 (3H, s), 6.82-6.86 (2H, m), 6.91-6.95 (1H, m).

Example 10

¹H-NMR (δ, CDCl₃):0.79 (3H, d, J=6.8Hz), 1.10-1.19 (1H, m) 1.19 (3H, d, J=6.8Hz), 1.46-1.57 (1H, m), 1.86 (1H, dt, J=4.4, 12.7Hz), 2.07 (1H, sept, J=6.8Hz), 2.08-2.17 (1H, m), 2.15 (3H, s), 2.27-2.40 (2H, m), 2.43-2.56 (2H, m), 3.37 (3H, s), 3.50-3.59 (6H, m), 3.89 (3H, s), 3.89 (3H, s), 6.83-6.86 (2H, m), 6.91-6.94 (1H, m).

Example 11 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-(N,N-diethylamino)-pentanenitrile

1.00 g (3.4 mmol) of 5-chloro-2-(3′,4′-dimethoxyphenyl)-2-isopropylpentanenitrile was dissolved in N,N-dimethylformamide, and 1.74 g (12.6 mmol) of potassium carbonate, 0.92 g (12.6 mmol) of diethylamine and 0.05 g of sodium iodide were added thereto. After being stirred at 100° C. for 72 hours, the solvent was evaporated out under a vacuum. The residue was extracted with ethyl acetate and washed three times with water until it became neutral. The organic layer was filtrated through 1PS filter paper, and the solvent was evaporated put. The residue was purified by silica gel column chromatography, to give 1.08 g (3.3 mmol, 96%) of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-(N,N-diethylamino)pentanenitrile.

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.95 (6H, t, J=7.0Hz), 1.08-1.21 (1H, m), 1.19 (3H, d, J=6.8Hz), 1.45-1.57 (1H, m), 1.85 (1H, dt, J=4.7, 12.8Hz), 2.03-2.15 (2H, m), 2.32-2.49 (6H, m), 3.89 (3H, s), 3.89 (3H, s), 6.83-6.86 (2H, m), 6.91-6.95 (1H, m).

Examples 12-18

In Example 11, in the place of diethylamine, a dialkylamine shown in Table 3 below can be used to synthesize each compound of Examples 12-15. TABLE 3

Example R¹⁻¹ Dialkylamine 12 -n-Pr n-Pr₂NH 13 -i-Pr i-Pr₂NH 14 -n-Bu n-Bu₂NH 15 -i-Bu i-Bu₂NH

Also, in Example 11, in the place of diethylamine, a cyclic amine shown in Table 4 can be used to synthesize each compound of Examples 16-18. TABLE 4

Example A Cyclic amine 16

17

18

The

¹H-NMR chemical shifts of Examples 12-18 are shown in below.

Example 12

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.83 (6H, t, J=7.3Hz), 1.06-1.17 (1H, m), 1.19 (3H, d, J=6.8Hz), 1.31-1.54 (5H, m), 1.83 (1H, dt, J=4.4, 12.8Hz), 2.07 (1H, sept, J=6.8Hz), 2.08-2.16 (1H, m), 2.24 (2H, t, J=7.3Hz), 2.25 (2H, t, J=7.3Hz), 2.34 (2H, t, J=6.8Hz), 3.89 (3H, s), 3.90 (3H, s), 6.83-6.87 (2H, m), 6.91-6.94 (1H, m).

Example 13

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.93 (6H, d, J=6.3Hz), 0.93 (6H, d, J=6.3Hz), 1.01-1.13 (1H, m), 1.18 (3H, d, J=6.8Hz), 1.36-1.50 (1H, m), 1.84 (1H, dt, J=4.4, 12.7Hz), 2.06 (1H, sept, J=6.8Hz), 2.07-2.16 (1H, m), 2.26-2.45 (2H, m), 2.82-2.96 (2H, m), 3.88 (3H, s), 3.89 (3H, s), 6.82-6.86 (2H, m), 6.91-6.94 (1H, m).

Example 14

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.88 (6H, t, J=7.3Hz), 1.06-1.38 (9H, m), 1.19 (3H, d, J=6.8Hz), 1.42-1.54 (1H, m), 1.78-1.86 (1H, m), 2.04-2.17 (2H, m), 2.21-2.39 (6H, m), 3.88 (3H, s), 3.90 (3H, s), 6.83-6.87 (2H, m), 6.91-6.94 (1H, m).

Example 15

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.83 (6H, d, J=6.3Hz), 0.85 (6H, d, J=6.3Hz), 0.99-1.11 (1H, m), 1.19 (3H, d, J=6.8Hz), 1.38-1.51 (1H, m), 1.57-1.68 (2H, m), 1.80 (1H, dt, J=4.4, 12.2Hz), 1.90-2.00 (4H, m), 2.08 (1H, sept, J=6.8Hz), 2.18-2.27 (3H, m), 3.89 (3H, s), 3.90 (3H, s), 6.83-6.87 (2H, m), 6.90-6.94 (1H, m).

Example 16

¹H-NMR (δ, CDCl₃):0.79 (3H, d, J=6.8Hz), 1.11-1.25 (1H, m), 1.20 (3H, d, J=6.8Hz), 1.51-1.64 (1H, m), 1.68-1.80 (4H, m), 1.89 (1H, dt, J=4.4, 12.8Hz), 2.08 (1H, sept, J=6.8Hz), 2.15 (1H, dt, J=4.4, 13.1 Hz), 2.28-2.51 (6H, m), 3.89 (3H, s), 3.89 (3H, s), 6.82-6.87 (2H, m), 6.91-6.96 (1H, m).

Example 17

¹H-NMR (δ, CDCl₃):0.79 (3H, d, J=6.8Hz), 1.10-1.20 (1H, m), 1.19 (3H, d, J=6.8Hz), 1.36-1.43 (2H, m), 1.46-1.62 (5H, m), 1.83 (1H, dt, J=4.4, 12.8Hz), 2.04-2.14 (2H, m), 2.16-2.32 (6H, m), 3.89 (3H, s), 3.89 (3H, s), 6.82-6.85 (2H, m), 6.90-6.94 (1H, m).

Example 18

¹H-NMR (δ, CDCl₃):0.79 (3H, d, J=6.8Hz), 1.09-1.20 (1H, m), 1.19 (3H, d, J=6.8Hz), 1.46-1.63 (9H, m), 1.86 (1H, dt, J=4.4, 12.3Hz), 2.02-2.16 (2H, m), 2.35-2.58 (6H, m), 3.89 (3H, s), 4.00 (3H, s), 6.82-6.87 (2H, m), 6.91-6.94 (1H, m).

Example 19 Synthesis of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile

5.80 g (20.0 mmol) of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile was dissolved in 50 ml of isopropanol, and 7.73 g (20.0 mmol) of di-p-toluoyl-D-tartaric acid was added thereto while being stirred. The mixture was cooled at −20° C. for 1 day, and the depositing crystals were collected by filtration. The first and second crystals were combined and suspended again in isopropanol and washed. The organic layers obtained by filtration were combined and the solvent was evaporated out. 50 ml of water was added to the residue and then 10 ml of 48% sodium hydroxide solution was further added while being cooled with ice. After being stirred for 10 minutes, the reaction mixture was extracted twice with 100 ml of ethyl acetate, and then washed with water. The organic layer was filtrated through 1PS filter paper and the solvent was evaporated out. The residue was purified by silica gel column chromatography, and dissolved in 20 ml of isopropanol. 2.90 g (7.5 mmol) of di-p-toluoyl-L-tartaric acid was added to the solution while being stirred. The solution was cooled at −20° C. for 1 day and the depositing crystals were collected by filtration, to give 3.57 g (26%, optical rotation (−) 69.0 (C=1.0, abs. EtOH)) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile di-p-toluoyl-L-tartarate.

20 ml of water was added to 3.57 g (5.3 mmol) of the diastereomeric salt and then 4 ml of 48% sodium hydroxide solution was further added while being cooled with ice. After being stirred for 10 minutes, the mixture was extracted twice with 50 ml of ethyl acetate, to give 1.45 g (5.0 mmol, 25%) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile.

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.5Hz), 1.20 (3H, d, J=6.5Hz), 1.14-1.23 (1H, m), 1.54-1.61 (1H, m), 1.86-1.95 (1H, m), 2.08 (1H, sept, J=6.5Hz), 2.14-2.22 (1H, m), 2.27 (1H, br-s), 2.37 (3H, s), 2.51-2.61 (2H, m), 3.88 (3H, s), 3.90 (3H, s), 6.83-6.6.87 (2H, m), 6.91-6.95 (1H, m).

Example 20 Synthesis of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methylbutyl) amino]-pentanenitrile

1.45 g (5.0 mmol) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile was dissolved in 5mi of dimethylformamide, and 0.83 g (6.0 mmol) of potassium carbonate was added thereto. After being stirred at room temperature for 10 minutes, the mixture, with 0.91 g (6.0 mmol) of isopentyl bromide added thereto, was stirred at room temperature for 16 hours. The solvent was evaporated out under a vacuum, and the residue was extracted with dichloromethane and washed with water until it became neutral. The organic layer was filtrated through 1PS filter paper and the solvent was evaporated put. The residue was purified by silica gel column chromatography, to give 0.81 g (2.2 mmol, 44%) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[methyl(3-methylbutyl)amino]-pentanenitrile.

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.86 (3H, d, J=6.8Hz), 0.87 (3H, d, J=6.8Hz), 1.10-1.19 (1H, m), 1.19 (3H, d, J=6.8Hz), 1.25-1.32 (2H, m), 1.46-1.57 (2H, m), 1.84 (1H, dt, J=4.4, 12.2Hz), 2.08 (3H, s), 2.03-2.34 (6H, m), 3.88 (3H, s), 3.89 (3H, s), 6.83-6.87 (2H, m), 6.91-6.95(1H, m).

Example 21 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methylbutyl)amino]-pentanenitrile hydrochloride

1.84 g (5.1 mmol) of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methyl butyl)amino]-pentanenitrile was dissolved in 2 ml of dioxane and then 2 ml of 4N hydrochloric acid-dioxane solution was added thereto while being cooled with ice. After the mixture was stirred for 5 minutes, the solvent was evaporated out, and then purified by azeotropy with toluene to give 2.02 g (5.1 mmol, quant.) of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5- [N-methyl-N-(3-methylbutyl)amino]-pentanenitrile hydrochloride.

¹H-NMR (δ, DMSO-d₆):0.70 (3H, d, J=6.8Hz), 0.81-0.87 (6H, m), 1.08-1.20 (3H, m), 1.18-1.32 (1H, m), 1.39-1.65 (4H, m), 2.06-2.26 (3H, m), 2.53-2.60 (3H, m), 2.81-3.13 (4H, m), 3.76 (3H, s), 3.80 (3H, s), 6.93-7.00 (3H, m), 10.44-10.55 (1H, m).

Example 22 Synthesis of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile hydrochloride

870 mg (3.0 mmol) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile was dissolved in 2 ml of dioxane, and 1.5 ml of 4N hydrochloric acid-dioxane solution was added thereto while being cooled with ice. After the mixture was stirred for 5 minutes, the solvent was evaporated out. The residue obtained by azeotropy with toluene was dissolved in hexane-diethyl ether and placed at −20° C. for 1 day. The depositing crystals were collected by filtration, to give 854 mg (2.6 mmol, 87%) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile hydrochloride.

¹H-NMR (δ, DMSO-d₆):0.69 (3H, d, J=6.3Hz), 1.11 (3H, d, J=6.3Hz), 1.13-1.24 (1H, m), 1.49-1.57 (1H, m), 2.09-2.17 (2H, m), 2.20 (1H, sept, J=6.3Hz), 2.42 (3H, s), 2.75-2.90 (2H, m), 3.76 (3H, s), 3.79(3H, s), 6.91-7.00 (3H, m), 8.85 (2H, br-s).

Example 23 Synthesis of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methylbutyl) amino]-pentanenitrile hydrochloride

807 mg (2.2 mmol) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methylbutyl)amino]-pentanenitrile was dissolved in 2 ml of dioxane and 1 ml of 4N hydrochloric acid-dioxane solution while being cooled with ice. After the mixture was stirred for 5 minutes, the solvent was evaporated out and then purified by azeotropy with toluene to give 885 mg (2.2 mmol, quant.) of (R)-2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(3-methylbutyl)amino]-pentanenitrile hydrochloride.

¹H-NMR (δ, DMSO-d₆):0.70 (3H, d, J=6.8Hz), 0.81-0.87 (6H, m), 1.08-1.20 (3H, m), 1.18-1.32 (1H, m), 1.39-1.65 (4H, m), 2.06-2.26 (3H, m), 2.53-2.60 (3H, m), 2.81-3.13 (4H, m), 3.76 (3H, s), 3.80 (3H, s), 6.93-7.00 (3H, m), 10.44-10.55 (1H, m).

Example 24 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-morpholine-4″-yl-pentanenitrile

In Example 11, in the place of diethylamine, morpholine was used to give the entitled compound.

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 1.11-1.19 (1H, m), 1.20 (3H, d, J=6.8Hz), 1.50-1.61 (1H, m), 1.87 (1H, dt, J=4.4, 12.9Hz), 2.08 (1H, sept, J=6.8Hz), 2.10-2.19 (1H, m), 2.25-2.35 (6H, m), 3.66 (4H, t, J=4.8Hz), 3.89(3H, s), 3.89 (3H, s), 6.82-6.86 (2H, m), 6.90-6.93(1H, m).

Example 25 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-pyrrole-1″-yl-pentanenitrile

1.00 g (3.4 mmol) of 5-chloro-2-(3′,4′-dimethoxyphenyl)-2-isopropylpentanenitrile was dissolved in N,N-dimethylformamide, and then 0.62 g (5.5 mmol) of potassium t-butoxide, 0.37 g (5.5 mmol) of pyrrole, 0.18 g (0.55 mmol) of tris(3,6-dioxaheptyl)amine and 0.05 g of sodium iodide were added thereto. After the mixture was heated and refluxed for 4 hours, the solvent was evaporated out under a vacuum. The residue was extracted with ethyl acetate and washed with water three times until it became neutral. The organic layer was filtrated through 1PS filter paper and the solvent was evaporated out. The residue was purified by silica gel column chromatography, to give 0.92 g (2.8 mmol, 83%) of the entitled compound.

¹H-NMR (δ, CDCl₃):0.76 (3H, d, J=6.8Hz), 1.15 (3H, d, J=6.8Hz), 1.39-1.51 (1H, m), 1.66 (1H, dt, J=4.4, 12.8Hz), 1.78-1.89 (1H, m), 2.00 (1H, sept, J=6.8Hz), 2.02-2.11 (1H, m), 3.72-3.79 (1H, m), 3.84(3H, s), 3.88 (3H, s), 3.86-3.94 (1H, m), 6.10-6.12 (2H, m), 6.52-6.54 (2H, m), 6.68 (1H, d, J=2.0Hz), 6.81-6.88 (2H, m).

Example 26 Synthesis of 2-(3′,4′-dimethoxyphenyl)-5-imidazole-1″-yl-2-isopropylpentanenitrile

In Example 25, in the place of pyrrole, imidazole was used to give the entitled compound.

¹H-NMR (δ, CDCl₃):0.77 (3H, d, J=6.8Hz), 1.16 (3H, d, J=6.8Hz), 1.41-1.53 (1H, m), 1.65 (1H, dt, J=4.4, 12.8Hz), 1.82-1.93 (1H, m), 2.00 (1H, sept, J=6.8Hz), 2.03-2.12 (1H, m), 3.85(3H, s), 3.89 (3H, s), 3.83-3.98 (2H, m), 6.70 (1H, s), 6.77 (1H, s), 6.84 (1H, s) , 6.84 (1H, s), 7.05(1H, s), 7.39 (1H, m).

Example 27 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-pyrazole-1″-yl-pentanenitrile

In Example 25, in the place of pyrrole, pyrazole was used to give the entitled compound.

¹H-NMR (δ, CDCl₃):0.77 (3H, d, J=6.8Hz), 1.15 (3H, d, J=6.8Hz), 1.53-1.65 (1H, m), 1.77 (1H, dt, J=4.4, 12.7Hz), 1.84-1.96 (1H, m), 2.01 (1H, sept, J=6.8Hz), 2.11 (1H, dt, J=4.0, 13.2Hz), 3.85 (3H, s), 3.88(3H, s), 4.06-4.15 (2H, m), 6.23-6.24 (1H, m), 6.71-6.72 (1H, m), 6.81-6.88 (2H, m), 7.28-7.30 (1H, m), 7.45-7.47 (1H, m).

Example 28 Synthesis of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-[N-methyl-N-(n-pentyl)amino]pentane nitrile

In Example 2, in the place of isopentyl bromide, n-pentyl bromide was used to give the entitled compound.

¹H-NMR (δ, CDCl₃):0.80 (3H, d, J=6.8Hz), 0.88 (3H, t, J=7.3Hz), 1.08-1.44 (7H, m), 1.19 (3H, d, J=6.8Hz), 1.47-1.56 (1H, m), 1,84 (1H, dt, J=4.4, 12.2Hz), 2.08 (3H, s), 2.04-2.31 (6H, m), 3.88 (3H, s), 3.89 (3H, s), 6.83-6.87 (2H, m), 6.91-6.95 (1H, m).

Further, compounds and manufacturing processes thereof in accordance with the present invention are exemplified.

Examples 29-33

In Example 2, in the place of isopentyl bromide, an alkyl halide shown in Table 5 below can be used to give each compound of Examples 29-33. TABLE 5

Example R²⁻² Alkyl halide 29 -tert-Bu tert-BuBr 30 -sec-Bu sec-BuBr 31 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 32 -neo-Pen CH₃C(CH₃)₂CH₂Br 33 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 34-46

In Example 1(3), in the place of 30% methylamine methanol solution, ethylamine 2-(3′,4′-dimethoxyphenyl)-5-ethylamino-2-isopropylpentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 6 below are used respectively, to give each compound of Examples 34-46. TABLE 6

Example R²⁻³ Alkyl halide 34 -n-Pr n-PrBr 35 -i-Pr i-PrBr 36 -n-Bu n-BuBr 37 -i-Bu i-BuBr 38 -n-Pen n-PenBr 39 -i-Pen i-PenBr 40 -EtOEt EtOEtCl 41 -EtOEtOMe MeOEtOEtOMs 42 -tert-Bu tert-BuBr 43 -sec-Bu sec-BuBr 44 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 45 -neo-Pen CH₃C(CH₃)₂CH₂Br 46 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 47-58

In Example 1(3), in the place of 30% methylamine methanol solution, propylamine is used to give 2(3′,4′-dimethoxyphenyl)-2-isopropyl-5-propylaminopentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 7 below are used respectively, to give each compound of Examples 47-58. TABLE 7

Example R²⁻⁴ Alkyl halide 47 -i-Pr i-PrBr 48 -n-Bu n-BuBr 49 -i-Bu i-BuBr 50 -n-Pen n-PenBr 51 -i-Pen i-PenBr 52 -EtOEt EtOEtCl 53 -EtOEtOMe MeOEtOEtOMs 54 -tert-Bu tert-BuBr 55 -sec-Bu sec-BuBr 56 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 57 -neo-Pen CH₃C(CH₃)₂CH₂Br 58 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 59-69

In Example 1(3), in the place of 30% methylamine methanol solution, isopropylamine is used to give 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-isopropylamino pentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 8 below are used respectively, to give each compound of Examples 59-69. TABLE 8

Example R²⁻⁵ Alkyl halide 59 -n-Bu n-BuBr 60 -i-Bu i-BuBr 61 -n-Pen n-PenBr 62 -i-Pen i-PenBr 63 -EtOEt EtOEtCl 64 -EtOEtOMe MeOEtOEtOMs 65 -tert-Bu tert-BuBr 66 -sec-Bu sec-BuBr 67 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 68 -neo-Pen CH₃C(CH₃)₂CH₂Br 69 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 70-79

In Example 1(3), in the place of 30% methylamine methanol solution, n-butylamine is used to give 5-butylamino-2-(3′,4′-dimethoxyphenyl)-2-isopropylpentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 9 below are used respectively, to give each compound of Examples 70-79. TABLE 9

Example R²⁻⁶ Alkyl halide 70 -i-Bu i-BuBr 71 -n-Pen n-PenBr 72 -i-Pen i-PenBr 73 -EtOEt EtOEtCl 74 -EtOEtOMe MeOEtOEtOMs 75 -tert-Bu tert-BuBr 76 -sec-Bu sec-BuBr 77 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 78 -neo-Pen CH₃C(CH₃)₂CH₂Br 79 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 80-88

In Example 1(3), in the place of 30% methylamine methanol solution, i-butylamine is used to give 2-(3′,4′-dimethoxyphenyl)-5-isobutylamino-2-isopropylpentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 10 below are used respectively, to give each compound of Examples 80-88. TABLE 10

Example R²⁻⁷ Alkyl halide 80 -n-Pen n-PenBr 81 -i-Pen i-PenBr 82 -EtOEt EtOEtCl 83 -EtOEtOMe MeOEtOEtOMs 84 -tert-Bu tert-BuBr 85 -sec-Bu sec-BuBr 86 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 87 -neo-Pen CH₃C(CH₃)₂CH₂Br 88 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 89-97

In Example 1(3), in the place of 30% methylamine methanol solution, n-pentylamine is used to give 2(3′,4′-dimethoxyphenyl)-2-isopropyl-5-pentylaminopentanenitrile.

In Example 2, using this compound in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile, the reaction with an alkyl halide shown in Table 11 below is effected in similar manner, to give each compound of Examples 89-97. TABLE 11

Example R²⁻⁸ Alkyl halide 89 -i-Pen i-PenBr 90 -n-Pen n-PenBr 91 -EtOEt EtOEtCl 92 -EtOEtOMe MeOEtOEtOMs 93 -tert-Bu tert-BuBr 94 -sec-Bu sec-BuBr 95 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 96 -neo-Pen CH₃C(CH₃)₂CH₂Br 97 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 98-104

In Example 1(3), in the place of 30% methylamine methanol solution, tert-butylamine is used to give 5-tert-butylamino-2-(3′,4′-dimethoxyphenyl)-2-isopropyl pentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 12 below are used respectively, to give each compound of Examples 98-104. TABLE 12

Example R²⁻⁹ Alkyl halide 98 -tert-Bu tert-BuBr 99 -EtOEt EtOEtCl 100 -EtOEtOMe MeOEtOEtOMs 101 -sec-Bu sec-BuBr 102 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 103 -nec-Pen CH₃C(CH₃)₂CH₂Br 104 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 105-110

In Example 1(3), in the place of 30% methylamine methanol solution, sec-butylamine is used to give 5-sec-butylamino-2-(3′,4′-dimethoxyphenyl)-2-isopropyl pentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 13 below are used respectively, to give each compound of Examples 105-110. TABLE 13

Example R²⁻¹¹ Alkyl halide 105 -sec-Bu sec-BuBr 106 -EtOEt EtOEtCl 107 -EtOEtOMe MeOEtOEtOMs 108 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 109 -nec-Pen CH₃C(CH₃)₂CH₂Br 110 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 111-115

In Example 1(3), in the place of 30% methylamine methanol solution, sec-pentylamine is used to give 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-(1″-methylbutyl amino)pentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 14 below are used respectively, to give each compound of Examples 111-115. TABLE 14

Example R²⁻¹¹ Alkyl halide 111 -sec-Pen CH₃CH₂CH₂CH(Br)CH₃ 112 -EtOEt EtOEtCl 113 -EtOEtOMe MeOEtOEtOMs 114 -neo-Pen CH₃C(CH₃)₂CH₂Br 115 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 116-119

In Example 1(3), in the place of 30% methylamine methanol solution, neopentylamine is used to give 2-(3′,4′-dimethoxyphenyl)-5-(2″,2″-dimethylpropylamino)-2-isopropylpentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 15 below are used respectively, to give each compound of Examples 116-119. TABLE 15

Example R²⁻¹² Alkyl halide 116 -nec-Pen CH₃C(CH₃)₂CH₂Br 117 -EtOEt EtOEtCl 118 -EtOEtOMe MeOEtOEtOMs 119 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃

Examples 120-122

In Example 1(3), in the place of 30% methylamine methanol solution, 3-aminopentane is used to give 2-(3′,4′-dimethoxyphenyl)-5-(1″-ethylpropylamino)-2-isopropylpentanenitrile.

In Example 2, in the place of 2-(3′,4′-dimethoxyphenyl)-2-isopropyl-5-methyl aminopentanenitrile and isopentyl bromide, this compound and an alkyl halide shown in Table 16 below are used respectively, to give each compound of Examples 120-122. TABLE 16

Example R²⁻¹³ Alkyl halide 120 -1-Ethylpropyl CH₃CH₂CH(Br)CH₂CH₃ 121 -EtOEt EtOEtCl 122 -EtOEtOMe MeOEtOEtOMs

In the following, Preparation Examples of the hair growth promoting composition in accordance with the present invention are shown. The compounding amount is expressed by wt % unless otherwise specified.

Preparation Example 1 Hair Growth Tonic

Example 21 0.5 Pyridoxine dioctanoate 0.1 Pantothenyl ethyl ether 0.2 Hinokitiol 0.05 Polyoxyethylene (12) polyoxypropylene (6) decyl tetradecyl 1.0 1-Menthol 0.1 Disinfectants Q.S. 1,3-Butylene glycol 3.0 Ethanol 70.0 Purified water Balance <Preparation Method>

Ethanol-soluble ingredients were dissolved into ethanol at room temperature while being stirred. Water-soluble ingredients were dissolved in purified water. The aqueous solution was added to the ethanol solution. After being homogeneously mixed, the mixture was filtrated.

Preparation Example 2 Hair Regrowth Promoting Liquid Lotion

Example 22 0.2 Carpronium chloride 1.0 Pantothenyl ethyl ether 0.5 Diphenhydramine hydrochloride 0.1 Hinokitiol 0.1 dl-α-Tocopheryl acetate 0.1 Salicylic acid 0.2 1-Menthol 0.2 Glycyrrhizinic acid 0.1 Sodium dl-pyrrolidonecarboxylate solution 1.0 Ethanol 70.0 Purified water Balance <Preparation Method>

Ethanol-soluble ingredients were dissolved into ethanol at room temperature while being stirred. Water-soluble ingredients were dissolved in purified water. The aqueous solution was added to the ethanol solution. After being uniformly mixed, the mixture was filtrated.

Preparation Example 3 Hair Growth Tonic

Example 23 0.5 wt % Pyridoxine dioctanoate 0.1 Pantothenyl ethyl ether 0.2 Hinokitiol 0.05 Polyoxyethylene (12) polyoxypropylene (6) decyl tetradecyl 1.0 1-Menthol 0.1 Disinfectants Q.S. 1,3-Butylene glycol 3.0 Ethanol 70.0 Purified water Balance <Preparation Method>

Ethanol-soluble ingredients were dissolved into ethanol at room temperature while being stirred. Water-soluble ingredients were dissolved in purified water. The aqueous solution was added to the ethanol solution. After being homogeneously mixed, the mixture was filtrated.

Preparation Example 4 Hair Growth Promoting Liquid Lotion

Example 21 0.2 Carpronium chloride 1.0 Pantothenyl ethyl ether 0.5 Diphenhydramine hydrochloride 0.1 Hinokitiol 0.1 dl-α-Tocopheryl acetate 0.1 Salicylic acid 0.2 1-Menthol 0.2 Glycyrrhizinic acid 0.1 Sodium dl-pyrrolidonecarboxylate solution 1.0 Ethanol 70.0 Purified water Balance <Preparation Method>

Ethanol-soluble ingredients were dissolved into ethanol at room temperature while being stirred. Water-soluble ingredients were dissolved in purified water. The aqueous solution was added to the ethanol solution. After being uniformly mixed, the mixture was filtrated.

Preparation Example 5 O/W Milky Lotion

(Phase B) Polyoxyethylene (60) hydrogenated castor oil 2.0 Glycerin 10.0 Dipropylene glycol 10.0 1,3-Butylene glycol 4.0 Example 22 0.1 Polyethylene glycol 1500 5.0 (Phase B) Isocetyl octanoate 10.0 Squalane 5.0 Vaseline 2.0 Propyl paraben 2.0 (Phase C) 1% Carboxyvinylpolymer aqueous solution 30.0 Sodium hexametaphosphate 0.03 Ion-exchanged water 8.35 (Phase D) Ion-exchanged water 4.5 (Phase E) Potassium hydroxide 0.12 Ion-exchanged water Balance <Preparation Method>

Phases A and B were heated and dissolved, separately. Both were mixed and treated with a homomixer, thereby obtaining a gel. Phase D was then gradually added to this gel and dispersed by a homomixer. Then, Phases C and E, which were mixed and dissolved in advance separately, were added to this gel dispersion successively. The mixture was emulsified by a homomixer to obtain an O/W milky lotion.

Preparation Example 6 Cream

(Phase A) N,N-Dimethyl-2-tetradecylamineoxide 2.5 Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Glyceryl monostealate 3.0 Polyoxyethylene (20) 2-octyldodecyl ether 3.0 Propyl paraben 0.3 Perfume 0.1 (Phase B) Example 21 1.0 Glycerin 8.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium hexametaphosphate 0.005 Ion-exchanged water Balance <Preparation Method>

Phases A and B were heated and dissolved, separately. Both were mixed and emulsified by a homomixer to obtain a cream.

Preparation Example 7 Aerosol Spray

(Stock solution) 95% Ethanol 50.0 Glycyrrhizic acid 0.1 Example 23 0.5 Swertia herb extract 0.1 Sodium lauryl sulfate 0.1 Polyoxyethylene (40) hydrogentated castor oil 0.5 Lactic acid Q.S. Sodium lactate Q.S. Perfume Q.S. Ion-exchanged water Balance (Filling formulation) Stock solution 50.0 Liquefied petroleum gas 50.0 <Preparation Method>

A stock solution was prepared by mixing and dissolving the ingredients of stock solution. This stock solution was filled into a can and a valve was fit thereto. The gas was filled into the can to obtain an aerosol spray.

Preparation Example 8 Shampoo

 (1) Sodium cocoylmethyltaurate 2.0  (2) Polyoxyethylene (8) oleyl ether 2.0  (3) Laurie acid diethanolamide 4.0  (4) Ethylene glycol fatty acid ester 1.0  (5) Glycerin 0.2  (6) Menthol 0.1  (7) Example 21 0.1  (8) Disodium edetate 0.1  (9) Perfume Q.S. (10) Purified water Balance <Preparation Method>

The ingredient (10) was heated up to 70° C., and the ingredients (1)-(9) were added thereto successively. The mixture was mixed and dissolved with stirring, and then cooled to obtain a shampoo.

Preparation Example 9 Rinse

(1) Stearyl trimethyl ammonium chloride 1.5 (2) Dimethyl polysiloxane (20 cs) 3.0 (3) Polyoxyethylene (10) oleyl ether 1.0 (4) Glycerin 5.0 (5) Example 22 0.5 (6) 4-tert-Butyl-4′-methoxydibenzoylmethane Q.S. (7) Ultraviolet absorber Q.S. (8) Purified water Balance <Preparation Method>

The water phase was prepared by adding the ingredients (1), (3) and (4) to the ingredient (8) and heating up to 70° C. The oil phase was prepared by heating and dissolving the other ingredients up to 70° C. The oil phase was added to the water phase and mixed with stirring by an emulsifier. The mixture was cooled to obtain a rinse.

Preparation Example 10 Scalp Treatment

(Stock solution) (1) Liquid paraffin 27.0 (2) Stearic acid 5.0 (3) Cetanol 5.0 (4) Sorbitan monooleate 2.0 (5) Polyoxyethylene sorbitan monooleate 3.0 (6) Example 22 0.1 (7) 1,3-Butylene glycol 5.0 (8) Antiseptic Q.S. (9) Purified water Balance (Filling formulation) Stock solution 50.0 Liquefied petroleum gas 50.0 <Preparation Method>

The ingredients (5) and (6) were dissolved into the ingredients (1) to (4). After being homogeneously dissolved with heating up to 80° C., the mixture was cooled down to 30° C. This mixture was added to the mixed solution of the ingredients (7) to (9), which was maintained at 30° C., and mixed with stirring to obtain a stock solution. This stock solution was filled into a can together with the propellant to obtain a scalp treatment.

As be explained above, the present invention provides a hair growth promoting composition having excellent effects on promoting hair regrowth, preventing or inhibiting hair loss, and the like in human by compounding specified phenylacetonitrile derivative as a effective ingredient thereto. 

1. A hair growth promoting composition comprising, as an effective ingredient, a phenylacetonitrile derivative or a pharmacologically acceptable salt thereof expressed by the following Formula (I):

wherein each of R¹ and R² is hydrogen atom, a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group or C2-10 acyl group, or NR¹R² may be a heterocycle having 3-7 members; R³ is a C₁₋₅ alkyl group; and each of R⁴, R⁵ and R⁶ is hydrogen atom or a C₁₋₄ alkoxy group.
 2. The hair growth promoting composition according to claim 1, wherein said phenylacetonitrile derivative is expressed by the following Formula (I-1):

wherein R¹ and R² are as defined in said Formula (I).
 3. The hair growth promoting composition according to claim 1, wherein one of R¹ and R² is hydrogen atom or an alkyl group and the other is an alkyl group.
 4. An external preparation for skin comprising a phenylacetonitrile derivative or a pharmacologically acceptable salt thereof expressed by the following Formula (I):

wherein each of R¹ and R² is hydrogen atom, a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group or C₂₋₁₀ acyl group, or NR¹R² may be a heterocycle having 3-7 members; R³ is a C₁₋₅ alkyl group; and each of R⁴, R⁵ and R⁶ is hydrogen atom or a C₁₋₄ alkoxy group.
 5. A phenylacetonitrile derivative or a pharmacologically acceptable salt thereof expressed by the following Formula (I-2):

wherein each of R⁷ and R⁸ is hydrogen atom, a C₁₋₅ alkyl group or a C₂₋₅ alkenyl group, or NR⁷R⁸ may be a nonaromatic heterocycle having 3-7 members containing one nitrogen atom or an aromatic heterocycle having 5-7 members containing 1-3 nitrogen atoms, and wherein when one of R⁷and R⁸ is hydrogen atom or methyl group, the other is C₂₋₅ alkyl group or C₂₋₅ alkenyl group.
 6. A method for promoting hair growth, which comprises applying an effective amount of the phenylacetonitrile derivative or the pharmacologically acceptable salt thereof expressed by said Formula (I) of claim 1 on skin of mammals.
 7. A method for promoting hair growth according to claim 6, wherein the skin of mammals is human scalp.
 8. The hair growth promoting composition according to claim 2, wherein one of R¹ and R² is hydrogen atom or an alkyl group and the other is an alkyl group. 